Neonatal seizures are abnormal electrical discharges in the central nervous system of neonates and usually manifest as stereotyped muscular activity or autonomic changes. Diagnosis is confirmed by electroencephalography; testing for causes is indicated. Treatment depends on the cause.
(See also Seizure Disorders in adults.)
Seizures occur in 1 to 5/1000 live births; incidence increases in preterm infants and in low-birth-weight infants (1, 2).
Seizures may be related to a serious neonatal issue and require immediate evaluation. Most neonatal seizures are focal, probably because generalization of electrical activity is impeded in neonates by lack of myelination and incomplete formation of dendrites and synapses in the brain.
Some neonates undergoing electroencephalography (EEG) to assess seizures or other symptoms of encephalopathy (eg, hypoactivity, decreased responsiveness) are found to have clinically silent seizures (≥ 20 seconds of rhythmic epileptiform electrical activity during an EEG but without any clinically visible seizure activity). Occasionally, clinically silent electrical activity is continuous and persists for > 20 minutes; at that point, it is defined as electrical status epilepticus.
General references
1. Vasudevan C, Levene M. Epidemiology and aetiology of neonatal seizures. Semin Fetal Neonatal Med. 2013;18(4):185–191. doi:10.1016/j.siny.2013.05.008
2. Sandoval Karamian AG, DiGiovine MP, Massey SL. Neonatal Seizures. Pediatr Rev. 2024;45(7):381-393. doi:10.1542/pir.2023-006016
Etiology of Neonatal Seizure Disorders
The abnormal central nervous system (CNS) electrical discharge may be caused by a
Primary intracranial process (eg, meningitis, ischemic stroke, encephalitis, intracranial hemorrhage, tumor, malformation)
Systemic problem (eg, hypoxia-ischemia, hypoglycemia, hypocalcemia, hyponatremia, other disorders of metabolism)
Seizures due to an intracranial process usually cannot be differentiated from seizures resulting from a systemic problem by their clinical features (eg, focal vs generalized).
Hypoxia-ischemia, the most common cause of neonatal seizures, may occur before, during, or after delivery (see Overview of Perinatal Respiratory Disorders). Such seizures may be severe and difficult to treat, but they tend to abate after approximately 3 to 4 days. When neonatal hypoxia is treated with therapeutic hypothermia (usually whole-body cooling), seizures may be less severe but may recur during rewarming.
Ischemic stroke is more likely to occur in neonates with polycythemia, thrombophilia due to a genetic disorder, or severe hypotension but may occur in neonates without any risk factors. Stroke occurs typically in the middle cerebral artery distribution or, if associated with hypotension, in watershed zones (ie, parts of the brain also known as border zones that are vascularized by 2 arteries). Seizures resulting from stroke tend to be focal and may cause apnea.
Neonatal infections such as meningitis and sepsis may cause seizures; in such cases, seizures are usually accompanied by other symptoms and signs. Intrauterine infections can also cause seizures because of maternal-fetal transmission. Group B streptococci and gram-negative bacteria are common causes of such infections in neonates. Encephalitis due to cytomegalovirus, herpes simplex virus, rubella virus, Treponema pallidum, Toxoplasma gondii, or Zika virus can also cause seizures.
Hypoglycemia is common among neonates whose mothers have diabetes, who are small for gestational age, or who have hypoxia-ischemia or other stresses. Seizures due to hypoglycemia tend to be focal and variable. Prolonged or recurrent hypoglycemia may permanently affect the CNS.
Intracranial hemorrhage, including subarachnoid, intracerebral, and intraventricular hemorrhage, may cause seizures. Intraventricular hemorrhage, which occurs more commonly in preterm infants, results from bleeding in the germinal matrix (an area that is adjacent to the ventricles and that gives rise to neurons and glial cells during development).
Hypernatremia can result from accidental oral or IV sodium chloride overload.
Hyponatremia can result from dilution (when too much water is given orally or IV particularly in the setting of hypovolemia, which, when severe enough, leads to increased antidiuretic hormone [ADH] levels despite the low serum osmolarity [nonosmotic ADH release]) or may follow sodium loss in stool or urine.
Hypocalcemia (serum calcium level < 7.5 mg/dL [< 1.87 mmol/L]) is usually accompanied by a serum phosphorus level of > 3 mg/dL (> 0.95 mmol/L) and can be otherwise asymptomatic. Risk factors for hypocalcemia include prematurity and a difficult birth. Hypocalcemia can also be a manifestation of DiGeorge syndrome (22q11.2 deletion syndrome).
Hypomagnesemia is a rare cause of seizures, which may occur when the serum magnesium level is < 1.4 mEq/L (< 0.7 mmol/L). Hypomagnesemia often occurs with hypocalcemia and should be considered in neonates with hypocalcemia if seizures continue after adequate calcium therapy.
Inborn errors of metabolism (eg, amino or organic aciduria) can cause neonatal seizures. Rarely, pyridoxine dependencypyridoxine dependency causes seizures; however, it must always be considered in neonates with refractory seizures. Pyridoxine dependency is readily treated with pyridoxine.dependency is readily treated with pyridoxine.
CNS malformations (eg, cavernous malformations, malformations of cortical development) can also cause seizures.
Maternal recreational substance use (eg, of cocaine, heroin, or diazepam) is an increasingly common problem; seizures can accompany acute withdrawal after birth.
Neonatal seizures may have genetic causes. Benign familial neonatal convulsion is a potassium channelopathy inherited in an autosomal dominant pattern. Early infantile epileptic encephalopathy (Ohtahara syndrome) is a rare disorder associated with a variety of mutations.
Symptoms and Signs of Neonatal Seizure Disorders
Neonatal seizures are usually focal and may be difficult to distinguish from normal neonatal activity because they are subtle and may sometimes manifest as chewing or bicycling automatisms. The International League Against Epilepsy (ILAE) classifies neonatal seizures into 3 subtypes (1):
Motor: Automatisms (such as the above), clonic, epileptic spasms, myoclonic, tonic
Nonmotor: Autonomic, behavior arrest
Sequential
In the motor and sequential subtypes, common manifestations include migratory clonic jerks of extremities, alternating hemiseizures, and primitive subcortical seizures (which cause respiratory arrest, chewing movements, persistent eye deviations or nystagmoid movements, and episodic changes in muscle tone). Generalized tonic-clonic seizures are uncommon. In the nonmotor subtype, direct motor manifestations are not seen; this subtype is characterized by autonomic changes in heart rate, blood pressure, or breathing patterns, whereas behavior arrest seizures involve a sudden cessation of movement and responsiveness.
Clinically silent electrical seizure activity is often present after a hypoxic-ischemic insult (including perinatal asphyxia or stroke) and in neonates with CNS infections, especially after initial antiseizure medication treatment, which is more likely to stop clinical manifestations than electrical seizure activity.
Symptoms and signs reference
1. Yozawitz E. Neonatal Seizures. N Engl J Med. 2023;388(18):1692-1700. doi:10.1056/NEJMra2300188
Diagnosis of Neonatal Seizure Disorders
Electroencephalography (EEG)
Laboratory testing (eg, serum glucose, electrolytes, cerebrospinal fluid [CSF] analysis, urine and blood cultures; sometimes genetic testing)
Usually cranial imaging
Evaluation begins with a detailed family history and a physical examination.
Jitteriness (alternating contraction and relaxation of opposing muscles in the extremities) must be distinguished from true seizure activity. Jitteriness is usually stimulus-induced and can be stopped by holding the extremity still; in contrast, seizures occur spontaneously, and motor activity is felt even when the extremity is held still.
EEG
EEG is essential, and at times recording may need to be prolonged, especially when it is difficult to determine whether the neonate is having seizures. EEG is also helpful for monitoring response to treatment.
EEG should capture periods of active and quiet sleep and thus may require ≥ 2 hours of recording. A normal EEG with expected variation during sleep stages is a good prognostic sign; an EEG with diffuse severe abnormalities (eg, suppressed voltage or burst suppression pattern) is a poor one.
Bedside EEG with video monitoring for ≥ 24 hours may detect ongoing clinically silent electrical seizures, particularly in the first few days after a CNS insult.
Laboratory tests
Laboratory tests to evaluate for underlying treatable disorders should be done immediately. Tests include pulse oximetry; measurement of serum glucose, sodium, potassium, chloride, bicarbonate, calcium, and magnesium; lumbar puncture for CSF analysis (cell count and differential, glucose, protein) and culture; and urine and blood cultures. CSF analysis, culture, and urine and blood cultures are done only when suspicion of sepsis is high or other tests are negative.
The need for other metabolic tests (eg, arterial pH, blood gases, serum bilirubin, urine amino or organic acids) or tests for recreational and illicit drugs (passed to the neonate transplacentally or by breastfeeding [chestfeeding]) depends on the clinical situation.
Genetic testing must be considered for neonates with recurrent or refractory seizures of undetermined cause.
Imaging tests
Imaging tests are typically performed unless the cause is immediately obvious (eg, glucose or electrolyte abnormality). MRI is preferred but may not be readily available; in such cases, head CT is performed.
For very sick infants who cannot be moved to radiology, bedside cranial ultrasound is an option; it can detect intraventricular but not subarachnoid hemorrhage. MRI or CT is done when infants are stable.
Head CT can detect intracranial bleeding and some brain malformations. MRI shows malformations more clearly and can detect ischemic tissue within a few hours of onset.
Magnetic resonance spectroscopy may help determine the extent of an ischemic injury or identify buildup of certain neurotransmitters associated with an underlying metabolic disorder.
Treatment of Neonatal Seizure Disorders
Treatment of underlying etiology
Antiseizure medications
Treatment of neonatal seizures is focused primarily on the underlying disorder and secondarily on seizures.
Treatment of the cause
For low serum glucose, 10% dextrose IV fluid is given, and the serum glucose level is monitored; additional infusions are given as needed but cautiously to avoid hyperglycemia.10% dextrose IV fluid is given, and the serum glucose level is monitored; additional infusions are given as needed but cautiously to avoid hyperglycemia.
For hypocalcemia, 10% calcium gluconate is given IV; this treatment can be repeated for persistent hypocalcemic seizures. Rate of 10% calcium gluconate is given IV; this treatment can be repeated for persistent hypocalcemic seizures. Rate ofcalcium gluconate infusion should not exceed 0.5 mL/minute (50 mg/minute); continuous cardiac monitoring is necessary during the infusion. Extravasation should be avoided because skin may slough.
For hypomagnesemia, 50% magnesium sulfate solution is given IM.
Bacterial infections are treated with IV antibiotics (choice of agent depends on culture and sensitivity results).
Herpes encephalitis is treated with IV acyclovir.is treated with IV acyclovir.
Hypoxic-ischemic encephalopathy is treated with therapeutic hypothermia for 72 hours.
Antiseizure medications
Antiseizure medications are used unless seizures stop quickly after correction of reversible disorders such as hypoglycemia, hypocalcemia, hypomagnesemia, hyponatremia, or hypernatremia.
Phenobarbital is the most commonly used medication; a loading dose is given IV. If seizures continue, smaller doses can be given every 15 to 30 minutes until seizures cease or until the maximum dose is reached. If seizures are persistent, maintenance therapy may be started. Phenobarbital is the most commonly used medication; a loading dose is given IV. If seizures continue, smaller doses can be given every 15 to 30 minutes until seizures cease or until the maximum dose is reached. If seizures are persistent, maintenance therapy may be started.Phenobarbital is continued IV, especially if seizures are frequent or prolonged. When the infant is stable, it can be given orally. Therapeutic serum levels of phenobarbital are 20 to 40 mcg/mL (85 to 170 micromol/L), but higher levels are sometimes needed at least temporarily (1).
Levetiracetam is used to treat neonatal seizures because it is less sedating than Levetiracetam is used to treat neonatal seizures because it is less sedating thanphenobarbital. It is given IV as a loading dose, and therapy may be continued IV or orally every 12 hours. Therapeutic levels are not well-established in the neonate (1).
Fosphenytoin can be used if seizures continue despite Fosphenytoin can be used if seizures continue despitephenobarbital and levetiracetam. The loading dose is given IV over 30 minutes to avoid hypotension and arrhythmias. A maintenance dose may be started every 12 hours and adjusted based on clinical response or serum levels. Oral phenytoin has poor oral bioavailability in infants and is generally avoided for long-term use (. The loading dose is given IV over 30 minutes to avoid hypotension and arrhythmias. A maintenance dose may be started every 12 hours and adjusted based on clinical response or serum levels. Oral phenytoin has poor oral bioavailability in infants and is generally avoided for long-term use (1).
IV Lorazepam may be used initially for a prolonged seizure or for resistant seizures and repeated at 5- to 10-minute intervals, up to 3 doses in any 8-hour period.IV Lorazepam may be used initially for a prolonged seizure or for resistant seizures and repeated at 5- to 10-minute intervals, up to 3 doses in any 8-hour period.
Neonates given IV antiseizure medications are closely observed; large doses and combinations of medications, particularly lorazepam plus phenobarbital, may result in respiratory depression.
The optimal duration of maintenance therapy is not known for any of the antiseizure medications and depends on the underlying etiology of seizures and on the presence of risk factors for seizure recurrence.
Treatment reference
1. Yozawitz E. Neonatal Seizures. N Engl J Med. 2023;388(18):1692-1700. doi:10.1056/NEJMra2300188
Prognosis for Neonatal Seizure Disorders
Prognosis depends on the etiology:
Long-term outcomes of neonatal seizures are variable, ranging from no neurologic abnormalities to developmental delay, intellectual disability, and epilepsy (1).
Most neonates with seizures due to a transient electrolyte disturbance (eg, hypocalcemia, hyponatremia) do well when seizures resolve after the disturbance is reversed and long-term antiseizure medications are not required.
Those with severe intraventricular hemorrhage have a high morbidity rate.
For idiopathic seizures or seizures due to brain malformations, earlier onset is associated with worse neurodevelopmental outcomes.
It is suspected, but not proved, that prolonged or frequent neonatal seizures may cause damage beyond that caused by the underlying disorder, especially hippocampal sclerosis. There is concern that the metabolic stress of prolonged nerve cell firing during lengthy seizures may cause additional brain damage. When caused by acute injuries to the brain such as hypoxia-ischemia, stroke, or infection, neonates may have a series of seizures, but seizures typically abate after about 3 to 4 days; they may recur months to years later if brain damage has occurred. Seizures due to other conditions may be more persistent during the neonatal period.
Prognosis reference
1. Westergren H, Finder M, Marell-Hesla H, Wickström R. Neurological outcomes and mortality after neonatal seizures with electroencephalographical verification. A systematic review. Eur J Paediatr Neurol. 2024;49:45-54. doi:10.1016/j.ejpn.2024.02.005
Key Points
Neonatal seizures usually occur in reaction to a systemic or central nervous system event (eg, hypoxia-ischemia, stroke, hemorrhage, infection, metabolic disorder, structural brain abnormality).
Neonatal seizures are usually focal and may be difficult to recognize; common manifestations include migratory clonic jerks of extremities, chewing movements, persistent eye deviations or nystagmoid movements, episodic changes in muscle tone, and autonomic disturbances.
Electroencephalography is essential for diagnosis; laboratory testing and neuroimaging are usually also done to identify the cause.
Treatment is directed at the underlying cause first, then at seizure cessation.
Give phenobarbital or levetiracetam if seizures do not stop when the cause is corrected; fosphenytoin and lorazepam may be added for persistent seizures.Give phenobarbital or levetiracetam if seizures do not stop when the cause is corrected; fosphenytoin and lorazepam may be added for persistent seizures.
